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At a glance

Rare and severe type of cholestasis liver disease, beginning in infancy and progressing to cirrhosis before adolescence.

Synonyms

PFIC Syndrome; Byler Disease; Fatal Intrahepatic Cholestasis; MDR 3 Deficiency; Progressive Intrahepatic Cholestasis with Elevated Serum Gamma-Glutamyltransferase Syndrome.

History

First described by Clayton, in 1965, in an Amish descendant of Jacob Byler.

Incidence

Estimated 1:50,000 to 1: 100,000. Fewer than 200 patients have been reported for the low-GGT PFIC, whereas less than 20 are known in the high-GGT PFIC type. It is a lethal medical condition in childhood if not treated. Males and females are affected equally. PFIC represents 10 to 15% of chronic cholestasis and accounts for approximately 10% of pediatric liver transplants.

Classification

There are five types recognized:

  • Cholestasis Progressive Familial Intrahepatic Type I (PFIC Syndrome Type I; Byler Disease; Fatal Intrahepatic Cholestasis): Low level of gamma-glutamyl transferase (GGT); gene ATP8B1 (previously termed FIC 1) mapped on 18q21.

  • Cholestasis Progressive Familial Intrahepatic Type II (PFIC Syndrome Type II): Low level of γGT; gene ABCB11 (previously termed BSEP) mapped on 2q24.

  • Cholestasis Progressive Familial Intrahepatic Type III (PFIC Syndrome Type III; MDR 3 Deficiency; Progressive Intrahepatic Cholestasis with Elevated Serum Gamma-Glutamyltransferase Syndrome): High level of γGT; gene ABCB4 mapped on 7q21.1.

  • Cholestasis Progressive Familial Intrahepatic Type IV: Normal or mildly increased γGT, gene TJP2 mapped on 9q21.11.

  • Cholestasis Progressive Familial Intrahepatic Type V (Cholestasis Progressive Familial Intrahepatic Neonatal form): Low or normal serum levels of γGT and increased α-fetoprotein; gene NR1H4 mapped on 12q23.1.

Genetic inheritance

Autosomal recessive (majority of patients), also autosomal dominant with variable penetrance, or sporadic. Type II is found in the Middle East, Greenland, and Sweden.

Pathophysiology

Mutations of the ATP8B1 encoding for the P-type ATPase 3 result in a reduction of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane leading to a reduction in the canalicular lumen due to a high concentration of bile salts and an increased concentration of bile acids in hepatocytes. Mutations of the ABCB11 gene, which encodes for the ATP-dependent transporter result in reduced bile salt secretion and bile flow leading to cholestasis. Mutations in the ABCB4 gene encoding for the MDR3 protein result in a high biliary bile salt to phosphatidylcholine ratio. The phosphatidylcholine prevents injury to the bile epithelium from hydrophobic bile salts. An altered bile salt/phospholipid ratio destabilizes micelles leading to cholesterol crystallization and lithogenicity of bile. Mutations in TJP2 gene encoding for the tight junction protein 2 or zona-occludens 2. This is a cytoplasmic component of cell-cell junctional complexes expressed in most epithelia where they create a link between the transmembrane tight junction proteins and the actin cytoskeleton to form tight junctions. The NR1H4 gene, ...

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